Isothiocyanate functional surfactants, formulations incorporating the same, and associated methods of use

ABSTRACT

An isothiocyanate functional surfactant, wherein the protonated form of the surfactant includes the structure of formula (IA): 
                         
wherein R 1  includes the structure of formula (IIA), (IIIA), or (IVA),
 
                         
wherein X includes an integer ranging from approximately 0 to approximately 20, wherein R 2  comprises a linear or branched aliphatic group containing approximately 8 to approximately 25 carbon atoms, and wherein R 3  comprises an aliphatic or aromatic group containing approximately 1 to approximately 20 carbon atoms and at least one—N═C═S group.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.15/353,260, entitled “ISOTHIOCYANATE FUNCTIONAL SURFACTANTS,FORMULATIONS INCORPORATING THE SAME, AND ASSOCIATED METHODS OF USE,”filed Nov. 16, 2016, which is a continuation-in-part of U.S. applicationSer. No. 15/297,304, entitled “ISOTHIOCYANATE FUNCTIONAL SURFACTANTFORMULATION AND ASSOCIATED METHOD OF USE,” filed Oct. 19, 2016, which isa continuation of U.S. application Ser. No. 14/594,788, filed Jan. 12,2015, which is a continuation of U.S. application Ser. No. 13/342,516,filed Jan. 3, 2012, now U.S. Pat. No. 8,933,119, which claims thebenefit of U.S. Provisional Application Ser. No. 61/502,067, filed Jun.28, 2011, and U.S. Provisional Application Ser. No. 61/429,325, filedJan. 3, 2011—all of which are hereby incorporated herein by reference intheir entirety, including all references cited therein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

REFERENCE TO A SEQUENCE LISTING

Not applicable.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates in general to isothiocyanate functionalsurfactants, formulations incorporating isothiocyanate functionalsurfactants, and associated methods of use—including, but not limitedto, chemopreventive, chemotherapeutic and/or chemoprotectiveapplications.

2. Background Art

Natural, semi-synthetic, and/or synthetic compounds having one or moreisothiocyanate functional groups and their associated uses have beenknown in the art for years and are the subject of a plurality of patentsand publications, including, but not limited to: U.S. Pat. No. 8,772,251entitled “Use Of Isothiocyanate Derivatives As Anti-Myeloma Agents,”U.S. Pat. No. 7,303,770 entitled “Cancer Chemoprotective Food Products,”U.S. Pat. No. 6,737,441 entitled “Treatment Of Helicobacter WithIsothiocyanates,” U.S. Pat. No. 6,340,784 entitled “Method For SelectiveIncrease Of The Anticarcinogenic Glucosinolates In Brassica Oleracea,”U.S. Pat. No. 6,166,003 entitled “Heterocyclic Compounds For CancerChemoprevention,” U.S. Pat. No. 5,411,986 entitled “ChemoprotectiveIsothiocyanates,” U.S. Pat. No. 5,114,969 entitled “Method Of InhibitingLung Tumors, Arylalkyl Isothiocyanates, And Method Of SynthesizingSame,” United States Patent Application Publication No. US 2013/0116203entitled “Isothiocyanates And Glucosinolate Compounds And Anti-TumorCompositions Containing Same,” United States Patent ApplicationPublication No. 2009/0081138 entitled “Cancer ChemoprotectiveCompositions And Natural Oils And Methods For Making Same,” and UnitedStates Patent Application Publication No. 2006/0127996 entitled “MethodOf Extraction Of Isothiocyanates Into Oil From Glucosinolate-ContainingPlants And Method Of Producing Products With Oil ContainingIsothiocyanates Extracted From Glucosinolate-Containing Plants,” all ofwhich are hereby incorporated herein by reference in theirentirety—including all references cited therein.

U.S. Pat. No. 8,772,251 appears to disclose the use of glucomoringin(GMG) and its des-thio-glucoside (GMG-ITC) for the preparation of amedicament for the treatment of myeloma. The chemical structures of GMGand GMG-ITC are provided below:

U.S. Pat. No. 7,303,770 appears to disclose vegetable sources that serveas chemoprotective agents. The chemoprotective agents disclosed are richin glucosinolate (i.e., metabolic precursors to isothiocyanates). Thevegetable sources are used to provide a dietary means of reducing thelevel of carcinogens in mammals.

U.S. Pat. No. 6,737,441 appears to disclose methods of preventing orinhibiting the growth of helicobacter pylori through the use of acomposition that comprises a glucosinolate, an isothiocyanate or aderivative or metabolite thereof. The '441 patent also appears todisclose methods of preventing or treating persistent chronic gastritis,ulcers and/or stomach cancer in subjects at risk for, or in need oftreatment thereof.

U.S. Pat. No. 6,340,784 appears to disclose a method for producingBrassica oleracea with elevated anticarcinogenic glucosinolatederivatives. The elevated levels are obtained by crossing wild Brassicaoleracea species with brassica oleracea breeding lines, and subsequentlyselecting hybrids with levels of 4-methylsulfinylbutyl and/or3-methylsulfinylpropyl glucosinolates elevated above that initiallyfound in brassica oleracea breeding lines. The invention also relates toedible brassica plants, such as broccoli plants, with elevated levels of4-methylsulfinylbutyl glucosinolate and/or 3-methylsulfinylpropylglucosinolates, and to seeds of such plants.

U.S. Pat. No. 6,166,003 appears to disclose a compound comprising aheterocyclic moiety, such as a thiophene, covalently attached to analkylene isothiocyanate moiety. The compound is reportedly effective toprevent the occurrence or progression of cancer or a precancerouscondition, and can be used for therapeutic or prophylactic purposes. Thecompound can be provided and administered in the form of apharmaceutical composition, a cosmetic, a food additive, supplement, orthe like. The '003 patent also discloses methods for synthesis and useof the chemopreventive compound.

U.S. Pat. No. 5,411,986 appears to disclose that sulforaphane has beenisolated and identified as a major and very potent phase II enzymeinducer in broccoli (brassica oleracea italica). Sulforaphane isdisclosed as a mono-functional inducer, inducing phase II enzymesselectively without the induction of aryl hydrocarbon receptor-dependentcytochromes P-450 (phase I enzymes). The '986 patent disclosessynthesizing analogues differing in the oxidation state of sulfur andthe number of methylene groups, wherein their inducer potencies weremeasured. Sulforaphane was identified as the most potent of theseanalogues. Other analogues having different substituent groups in placeof the methylsulfinyl group of sulforaphane were also synthesized andassessed. Of these, the most potent were 6-isothiocyanato-2-hexanone andexo-2-acetyl-6-isothiocyanatonorbornane.

U.S. Pat. No. 5,114,969 appears to disclose a method of inhibiting lungtumor multiplicity and/or incidence by treating mammals with relativelylong chain arylalkyl isothiocyanates, especially effective with respectto tumors induced by exposure to tobacco-specific nitrosamine. Among theisothiocyanates disclosed are 4-phenylbutyl isothiocyanate, phenylpentylisothiocyanate and phenylhexyl isothiocyanate, which are synthesized byadding hydrochloride of phenylbutylamine, phenylpentylamine, orphenylhexylamine in water to thiophosgene in an inert organic solvent.

United States Patent Application Publication No. 2013/0116203 appears todisclose glucosinolate and isothiocyanate compounds and related methodsfor synthesizing these compounds and analogs. In certain embodiments,these glucosinolate and isothiocyanate compounds are useful andchemopreventive and or chemotherapeutic agents. Examples includecompounds of Formula I: R—N═C═S (I) wherein R is selected from the groupconsisting of dimethylpropyl, C₃-C₁₀ mono- or bicycloalkyl, C₆-C₁₀ mono-or bicycloakenyl, halobenzyl, alkyloxybenzyl, tetrahydronaphthalenyl,biphenyl-C₁-C₆-alkyl, phenoxybenzyl-C₁-C₆-alkyl, andpyridinyl-C₁-C₆-alkyl; N-acetyl cysteine conjugates thereof; and saltsthereof.

United States Patent Application Publication No. 2009/0081138 appears todisclose chemoprotective compositions containing reduced oil-contentextraction meals made from plants containing natural oils andglucosinolates. The oil content of the extraction meals may be reducedusing batchwise or continuous supercritical fluid extractions. Alsoprovided are glucosinolate-rich compositions containing purifiedglucosinolates isolated from plant materials. The glucosinolate-richcompositions may be made by reducing the oil content of a plantmaterials containing natural oils and glucosinolates and isolating theglucosinolates from the reduced oil-content plant materials using amembrane extraction. Natural oils containing isothiocyanates are alsoprovided.

United States Patent Application Publication No. 2006/0127996 appears todisclose a method of extraction of isothiocyanates into oil fromglucosinolate-containing plants and method of producing products withoil containing isothiocyanates extracted from glucosinolate-containingplants.

While the above-identified patents and publications do appear todisclose natural, semi-synthetic, and/or synthetic compounds having oneor more isothiocyanate functional groups associated with a plurality ofapplications and/or uses, none of the above-identified patents and/orpublications disclose isothiocyanate functional surfactants derived fromnatural and/or non-natural amino acids, including, but not limited to,L-lysine, L-ornithine, etcetera.

It is therefore an object of the present invention to provide novelisothiocyanate functional surfactants that will partially and/or fullyremedy problems and/or complications associated with non-surfactantderived isothiocyanate functional compounds. It is therefore anadditional object of the present invention to provide novel formulationsincorporating isothiocyanate functional surfactants, and associatednovel methods of use.

These and other objects of the present invention will become apparent inlight of the present specification, claims, chemical structures,chemical formulae, and drawings.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to anisothiocyanate functional surfactant, wherein said isothiocyanatefunctional surfactant comprises at least one isothiocyanate functionalgroup associated with an aliphatic and/or aromatic carbon atom of theisothiocyanate functional surfactant.

The present invention is also directed to a lysine or ornithinederivative, wherein the lysine or ornithine derivative comprises anα-nitrogen and a ε-nitrogen, and wherein an alkyl and/or alkanoylsubstituent comprising at least approximately 8 carbon atoms isassociated with the α-nitrogen, and further wherein at least oneisothiocyanate functional group is associated with the ε-nitrogen.

The present invention is further directed to an isothiocyanatefunctional surfactant comprising a surfactant or a pharmaceuticallyacceptable salt thereof, wherein the protonated form of the surfactantcomprises the structure of formula (IA):

wherein R₁ comprises the structure of formula (IIA), (IIIA), or (IVA);

wherein X comprises an integer ranging from approximately 0 toapproximately 20; wherein R₂ comprises a linear or branched aliphaticgroup containing at least approximately 8 to approximately 25 carbonatoms; and wherein R₃ comprises an aliphatic or aromatic groupcontaining approximately 1 to approximately 20 carbon atoms and at leastone—N═C═S group.

In a preferred embodiment of the present invention, R₁ of formula (IA)comprises the structure of formula (IIA).

In another preferred embodiment of the present invention, R₁ of formula(IA) comprises the structure of formula (IIIA).

In yet another preferred embodiment of the present invention, R₁ offormula (IA) comprises the structure of formula (IVA). In thisembodiment R₂ of formula (IA) preferably comprises an aliphatic groupcontaining at least approximately 12 to approximately 20 carbon atoms.

The present invention is further directed to an isothiocyanatefunctional surfactant comprising a surfactant or a pharmaceuticallyacceptable salt thereof, wherein the surfactant comprises the structureof formula (IB):

wherein R₁ comprises the structure of formula (IIB), (IIIB), or (IVB);

wherein X comprises an integer ranging from approximately 0 toapproximately 20; wherein R₂ comprises a linear or branched aliphaticgroup containing at least approximately 8 to approximately 25 carbonatoms; wherein R₃ comprises an aliphatic or aromatic group containingapproximately 1 to approximately 20 carbon atoms and at least one—N═C═Sgroup; and wherein M⁺ comprises a counter cation such as, but notlimited to, H⁺, alkali metals (e.g., Li⁺, Na⁺, K⁺), alkaline earthmetals, transition metals, s-block metals, d-block metals, p-blockmetals, NZ₄ ⁺, wherein Z comprises, H, R₄, OR₄, and wherein R₄ comprisesan alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl,aralkyl, alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano groupcontaining approximately 1 to approximately 25 carbon atom(s).

In a preferred embodiment of the present invention, R₁ of formula (IB)comprises the structure of formula (IIB).

In another preferred embodiment of the present invention, R₁ of formula(IB) comprises the structure of formula (IIIB).

In yet another preferred embodiment of the present invention, R₁ offormula (IB) comprises the structure of formula (IVB). In thisembodiment R₂ of formula (IB) preferably comprises an aliphatic groupcontaining at least approximately 12 to approximately 20 carbon atoms.

The present invention is also directed to an isothiocyanate functionalsurfactant formulation comprising a surfactant or a pharmaceuticallyacceptable salt thereof, wherein the surfactant comprises the structureof formula (IB):

wherein R₁ comprises the structure of formula (IIB), (IIIB), or (IVB);

wherein X comprises an integer ranging from approximately 0 toapproximately 20; wherein R₂ comprises a linear or branched aliphaticgroup containing at least approximately 8 to approximately 25 carbonatoms; wherein R₃ comprises an aliphatic or aromatic group containingapproximately 1 to approximately 20 carbon atoms and at least one—N═C═Sgroup; wherein M⁺ comprises a counter cation such as, but not limitedto, H⁺, alkali metals (e.g., Li⁺, Na⁺, K⁺), alkaline earth metals,transition metals, s-block metals, d-block metals, p-block metals, NZ₄⁺, wherein Z comprises, H, R₄, OR₄, and wherein R₄ comprises an alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano group containingapproximately 1 to approximately 25 carbon atom(s); and anon-hygroscopic solvent.

In a preferred embodiment of the present invention, R₁ of formula (IB)comprises the structure of formula (IIB).

In another preferred embodiment of the present invention, R₁ of formula(IB) comprises the structure of formula (IIIB).

In yet another preferred embodiment of the present invention, R₁ offormula (IB) comprises the structure of formula (IVB). In thisembodiment R₂ of formula (IB) preferably comprises an aliphatic groupcontaining at least approximately 12 to approximately 20 carbon atoms,and the non-hygroscopic solvent comprises a hydrocarbon ornon-hydrocarbon based oil.

DETAILED DESCRIPTION OF THE INVENTION

While this invention is susceptible of embodiment in many differentforms, there is shown in the drawings and described herein in detailseveral specific embodiments with the understanding that the presentdisclosure is to be considered as an exemplification of the principlesof the invention and is not intended to limit the invention to theembodiments illustrated.

As is discussed in greater detail herein, the present invention isdirected toward isothiocyanate functional surfactants. Preferably, thesesurfactants serve as chemopreventive, chemotherapeutic and/orchemoprotective agents. However, the isothiocyanate functionalsurfactants of the present invention may also, and/or alternatively, beused to treat a plurality of conditions, including, but not limited to,acne, alopecia areata, basal cell carcinoma, bowen's disease, congenitalerythropoietic porphyria, contact dermatitis, darier's disease,dystrophic epidermolysis bullosa, eczema, epidermolysis bullosa simplex,erythropoietic protoporphyria, fungal infections of nails, hailey-haileydisease, herpes simplex, hidradenitis suppurativa, hirsutism,hyperhidrosis, ichthyosis, impetigo, keloids, keratosis pilaris, lichenplanus, lichen sclerosus, melanoma, melisma, pemphigus vulgaris,phytophotodermatitis, plantar warts, pityriasis lichenoides, polymorphiclight eruption, psoriasis, pyoderma gangrenosum, rosacea, scabies,shingles, squamous cell carcinoma, sweet's syndrome, and vitiligo—justto name a few. The present invention also includes formulations thatutilize isothiocyanate functional surfactants.

It will be understood that term surfactant is derived from thecontraction of the terms surface-active-agent and is defined herein as amolecule and/or group of molecules which are able to modify theinterfacial properties of the liquids (aqueous and non-aqueous) in whichthey are present. The surfactant properties of these molecules reside intheir amphiphilic character which stems from the fact that eachsurfactant molecule has both a hydrophilic moiety and a hydrophobic (orlipophilic) moiety, and that the extent of each of these moieties isbalanced so that at concentrations at or below the critical micelleconcentration (i.e., CMC) they generally concentrate at the air-liquidinterface and materially decrease the interfacial tension. For example,sodium salts of saturated carboxylic acids are extremely soluble inwater up to C8 length and are thus not generally regarded as truesurfactants. They become less soluble in water from C9 up to C18 length,the domain of effective surfactants for this class of compounds. Thecarboxylic acids (fatty acids) can be either saturated or unsaturatedstarting from C16 chain lengths.

Without being bound by any one particular theory, it is believed thatthe isothiocyanate functional surfactants disclosed herein serve asmedicaments and/or chemopreventive, chemotherapeutic and/orchemoprotective agents by altering, modifying, and/or boosting thebody's immune system. It is also believed that the isothiocyanatefunctional surfactants disclosed herein facilitate elevating phase IIenzymes (e.g., HAD(P)H quinine oxidoreductase) which are believed to,among other things regulate inflammatory responses within the body, aswell as detoxify potential and active carcinogens.

In accordance with the present invention, the isothiocyanate functionalsurfactants may be used as a topical leave-on product in which one ormore surfactants remain on the skin and are not immediately and/or everrinsed off away from the skin. Alternatively, the isothiocyanatefunctional surfactants of the present invention may be used as a topicalwash in an apply-and-rinse fashion. For either case, it is preferredthat the isothiocyanate functional surfactants be generally mild tohuman skin (e.g., non-irritating or low-irritating). In particular,anionic N-alkanoyl surfactants derived from amino acids are especiallypreferred because, while not completely predictable, they have atendency to be mild. The methods of preparation detailed in thisinvention employ, but are not limited to, amino acids that possess atleast two amine functionalities, at least one of which is converted toan N-alkanoyl functionality, and at least one of which is converted intoisothiocyanate functionality. The amino acids include, but are notlimited to, the α-amino acids lysine, ornithine, 2,4-diaminobutanoicacid, 2,3-diaminoproprionic acid, 2,7-diaminoheptanoic acid, and2,8-diaminooctanoic acid. Additionally, amino acids other than α-aminoacids may be employed, such as β-amino acids, etcetera. It will beunderstood that amino acid derived surfactants are preferred due totheir mild nature, but any one of a number of other surfactants arelikewise contemplated for use in accordance with the present invention.

The methods for preparing isothiocyanate functional surfactants and/ortheir precursors can involve, but are not limited to, conversion of anamine functionality to an isothiocyanate functionality. The methods ofconversion of amine functionalities to isothiocyanate functionalitiesmay comprise, but are not limited to: (1) reaction with carbon disulfideto yield an intermediate dithiocarbamate, followed by reaction withethylchloroformate or its functional equivalent such asbis(trichloromethyl)-carbonate, trichloromethyl chloroformate, orphosgene; (2) reaction with thiophosgene; (3) reaction with1,1′-thiocarbonyldiimidizole; (4) reaction with phenylthiochloroformate;(5) reaction with ammonium or alkali metal thiocyanate to prepare anintermediate thiourea followed by cleaving to the isothiocyanate viaheating; and (6) reaction with an isothiocyanato acyl halide[SCN—(CH₂)_(n)—CO—Cl]. The resulting isothiocyanate functionalsurfactant, depending on the method of preparation, can be isolated as apure material or as a mixture with other surfactants. The resultingisothiocyanate functional surfactant, depending on the method ofpreparation, can be isolated and used directly in nonionic form, anionicform, cationic form, zwitterionic (amphoteric) form, or in a neutralsurfactant-precursor form in combination with a base such as sodiumhydroxide or triethanol amine if the neutral surfactant-precursor formpossesses a protonated carboxylic acid group such that reaction(deprotonation) with the base converts the neutral surfactant-precursorform to an anionic surfactant, or in neutral surfactant-precursor formin combination with an acid if the neutral surfactant-precursor formpossess amine functionality such that reaction (protonation) with theacid converts the neutral surfactant-precursor form to a cationicsurfactant.

In accordance with the present invention the isothiocyanate functionalsurfactants can be applied and/or associated with a human using any oneof a number of techniques including, but not limited to, spraying,dripping, dabbing, rubbing, blotting, dipping, and any combinationthereof.

In certain preferred embodiments of the present invention, theisothiocyanate functional surfactants are removed from the affected areaafter a period of time. Such a period comprises, but is not limited to,seconds (e.g., 1 second, 2 seconds, 5 seconds, 10 seconds, 15 seconds,20 seconds, 30 seconds, 45 seconds, and 60 seconds), minutes (e.g., 1minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30minutes, 45 minutes, and 60 minutes), hours (e.g., 1 hour, 2 hours, 5hours, 10 hours, 15 hours, 20 hours, 30 hours, 45 hours, and 60 hours),days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10days, 14 days, 21 days, 30 days), etcetera. It will be understood thatthe step of removing preferably occurs via rinsing, wiping, and/orextracting—just to name a few.

Depending upon the subject and/or the severity of the medical condition,multiple applications may be necessary. As such, the steps of applyingand/or removing the isothiocyanate functional surfactants may berepeated once or a plurality of times.

In one embodiment, the present invention is directed to anisothiocyanate functional surfactant, wherein said isothiocyanatefunctional surfactant comprises at least one isothiocyanate functionalgroup associated with an aliphatic and/or aromatic carbon atom of theisothiocyanate functional surfactant.

The present invention is also directed to a lysine derivative, whereinthe lysine derivative comprises an α-nitrogen and a ε-nitrogen, andwherein an alkyl and/or alkanoyl substituent comprising at leastapproximately 8 carbon atoms is associated with the α-nitrogen, andfurther wherein at least one isothiocyanate functional group isassociated with the ε-nitrogen.

The present invention is further directed to a novel isothiocyanatefunctional surfactant comprising: a surfactant or a pharmaceuticallyacceptable salt thereof, wherein the protonated form of the surfactantcomprises the structure of formula (IA):

wherein R₁ comprises the structure of formula (IIA), (IIIA), or (IVA);

wherein X comprises an integer ranging from approximately 0 toapproximately 20; wherein R₂ comprises a linear or branched aliphaticgroup containing at least approximately 8 to approximately 25 carbonatoms; and wherein R₃ comprises an aliphatic or aromatic groupcontaining approximately 1 to approximately 20 carbon atoms and at leastone—N═C═S group.

More preferably, the surfactant is represented by one or more of thefollowing chemical structures:

In another embodiment, the present invention is directed to anisothiocyanate functional surfactant comprising: a surfactant or apharmaceutically acceptable salt thereof, wherein the surfactantcomprises the structure of formula (IB):

wherein R₁ comprises the structure of formula (IIB), (IIIB), or (IVB);

wherein X comprises an integer ranging from approximately 0 toapproximately 20; wherein R₂ comprises a linear or branched aliphaticgroup containing at least approximately 8 to approximately 25 carbonatoms; wherein R₃ comprises an aliphatic or aromatic group containingapproximately 1 to approximately 20 carbon atoms and at least one —N═C═Sgroup; and wherein M⁺ comprises a counter cation such as, but notlimited to, H⁺, alkali metals (e.g., Li⁺, Na⁺, K⁺), alkaline earthmetals, transition metals, s-block metals, d-block metals, p-blockmetals, NZ₄ ⁺, wherein Z comprises, H, R₄, OR₄, and wherein R₄ comprisesan alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl,aralkyl, alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano groupcontaining approximately 1 to approximately 25 carbon atom(s).

In yet another embodiment, the present invention is directed to anisothiocyanate functional surfactant formulation comprising: asurfactant or a pharmaceutically acceptable salt thereof, wherein thesurfactant comprises the structure of formula (IB):

wherein R₁ comprises the structure of formula (IIB), (IIIB), or (IVB);

wherein X comprises an integer ranging from approximately 0 toapproximately 20; wherein R₂ comprises a linear or branched aliphaticgroup containing at least approximately 8 to approximately 25 carbonatoms; wherein R₃ comprises an aliphatic or aromatic group containingapproximately 1 to approximately 20 carbon atoms and at least one—N═C═Sgroup; wherein M⁺ comprises a counter cation such as, but not limitedto, H⁺, alkali metals (e.g., Li⁺, Na⁺, K⁺), alkaline earth metals,transition metals, s-block metals, d-block metals, p-block metals, NZ₄⁺, wherein Z comprises, H, R₄, OR₄, and wherein R₄ comprises an alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkanoyl, aroyl, alkenyl, alkynyl and/or cyano group containingapproximately 1 to approximately 25 carbon atom(s); and anon-hygroscopic solvent.

In accordance with the present invention, the isothiocyanate functionalsurfactant may be associated with an additional surfactant, wherein theadditional surfactant is selected from at least one of the groupcomprising a non-ionic surfactant, an anionic surfactant, a cationicsurfactant, a zwitterionic surfactant, and combinations thereof.

Non-limiting examples of preferred anionic surfactants include taurates;isethionates; alkyl and alkyl ether sulfates; succinamates; alkylsulfonates, alkylaryl sulfonates; olefin sulfonates; alkoxy alkanesulfonates; sodium and potassium salts of fatty acids derived fromnatural plant or animal sources or synthetically prepared; sodium,potassium, ammonium, and alkylated ammonium salts of alkylated andacylated amino acids and peptides; alkylated sulfoacetates; alkylatedsulfosuccinates; acylglyceride sulfonates, alkoxyether sulfonates;phosphoric acid esters; phospholipids; and combinations thereof.Specific anionic surfactants contemplated for use include, but are by nomeans limited to, ammonium cocoyl isethionate, sodium cocoylisethionate, sodium lauroyl isethionate, sodium stearoyl isethionate,sodium lauroyl sarcosinate, sodium cocoyl sarcosinate, sodium laurylsarcosinate, disodium laureth sulfosuccinate, sodium laurylsulfoacetate, sodium cocoyl glutamate, TEA-cocoyl glutamate, TEA cocoylalaninate, sodium cocoyl taurate, potassium cetyl phosphate.

Non-limiting examples of preferred cationic surfactants includealkylated quaternary ammonium salts R₄NX; alkylated amino-amides(RCONH—(CH₂)_(n))NR₃X; alkylimidazolines; alkoxylated amines; andcombinations thereof. Specific examples of anionic surfactantscontemplated for use include, but are by no means limited to, cetylammonium chloride, cetyl ammonium bromide, lauryl ammonium chloride,lauryl ammonium bromide, stearyl ammonium chloride, stearyl ammoniumbromide, cetyl dimethyl ammonium chloride, cetyl dimethyl ammoniumbromide, lauryl dimethyl ammonium chloride, lauryl dimethyl ammoniumbromide, stearyl dimethyl ammonium chloride, stearyl dimethyl ammoniumbromide, cetyl trimethyl ammonium chloride, cetyl trimethyl ammoniumbromide, lauryl trimethyl ammonium chloride, lauryl trimethyl ammoniumbromide, stearyl trimethyl ammonium chloride, stearyl trimethyl ammoniumbromide, lauryl dimethyl ammonium chloride, stearyl dimethyl cetylditallow dimethyl ammonium chloride, dicetyl ammonium chloride, dilaurylammonium chloride, dilauryl ammonium bromide, distearyl ammoniumchloride, distearyl ammonium bromide, dicetyl methyl ammonium chloride,dicetyl methyl ammonium bromide, dilauryl methyl ammonium chloride,distearyl methyl ammonium chloride, distearyl methyl ammonium bromide,ditallow dimethyl ammonium chloride, ditallow dimethyl ammonium sulfate,di(hydrogenated tallow) dimethyl ammonium chloride, di(hydrogenatedtallow) dimethyl ammonium acetate, ditallow dipropyl ammonium phosphate,ditallow dimethyl ammonium nitrate, di(coconutalkyl)dimethyl ammoniumchloride, di(coconutalkyl)dimethyl ammonium bromide, tallow ammoniumchloride, coconut ammonium chloride, stearamidopropyl PG-imoniumchloride phosphate, stearamidopropyl ethyldimonium ethosulfate,stearimidopropyldimethyl (myristyl acetate) ammonium chloride,stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyldimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate,ditallowyl oxyethyl dimethyl ammonium chloride, behenamidopropyl PGdimonium chloride, dilauryl dimethyl ammonium chloride, distearlydimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride,dipalmityl dimethyl ammonium chloride, distearyl dimethyl ammoniumchloride, stearamidoproyl PG-dimonium chloride phosphate,stearamidopropyl ethyldiammonium ethosulfate, stearamidopropyl dimethyl(myristyl acetate) ammonium chloride, stearimidopropyl diemthyl cetarylammonium tosylate, stearamido propyl dimethyl ammonium chloride,stearamidopropyl dimethyl ammonium lactate.

Non-limiting examples of preferred non-ionic surfactants includealcohols, alkanolamides, amine oxides, esters (including glycerides,ethoxylated glycerides, polyglyceryl esters, sorbitan esters,carbohydrate esters, ethoxylated carboxylic acids, phosphoric acidtriesters), ethers (including ethoxylated alcohols, alkyl glucosides,ethoxylated polypropylene oxide ethers, alkylated polyethylene oxides,alkylated polypropylene oxides, alkylated PEG/PPO copolymers), siliconecopolyols. Specific examples of non-ionic surfactants contemplated foruse include, but are by no means limited to, cetearyl alcohol,ceteareth-20, nonoxynol-9, C12-15 pareth-9, POE(4) lauryl ether,cocamide DEA, glycol distearate, glyceryl stearate, PEG-100 stearate,sorbitan stearate, PEG-8 laurate, polyglyceryl-10 trilaurate, laurylglucoside, octylphenoxy-polyethoxyethanol, PEG-4 laurate, polyglyceryldiisostearate, polysorbate-60, PEG-200 isostearyl palmitate, sorbitanmonooleate, polysorbate-80.

Non-limiting examples of preferred zwitterionic or amphotericsurfactants include betaines; sultaines; hydroxysultaines, amidobetaines, amidosulfo betaines; and combinations thereof. Specificexamples of amphoteric surfactants contemplated for use include, but areby no means limited to, cocoamidopropyl sultaine, cocoamidopropylhydroxyl sultaine, cocoamidopropylbetaine, coco dimethyl carboxymethylbetaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethylalphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyldimethyl betaine, lauryl (2-bishydroxy) carboxymethyl betaine, stearylbis-(2-hydroxyethyl) carboxymethyl betaine, oleyl dimethylgamma-carboxypropyl betaine, lauryl bis-(2-hydroxypropyl)alphacarboxymethyl betaine, coco dimethyl sulfopropyl betaine, stearyldimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, laurylbis(2-hydroxyethyl) sulfopropyl betaine, oleyl betaine, cocamidopropylbetaine.

In further accordance with the present invention, the isothiocyanatefunctional surfactant may be incorporated into a formulation comprisingone or more solvents. Preferably, the solvent comprises a hydrocarbonand/or silicone oil that is generally non-hygroscopic and/or generallyhydrophobic. Suitable examples, include, silicone based solvents and/orfluids, mineral oil, vegetable oils, squalene (i.e.,2,6,10,15,19,23-hexamethyltetracosane)—just to name a few.

The invention is further described by the following examples.

Example I Preparation of a Mixture ofN_(α)-lauroyl-N_(ε)-Isothiocyanato-L-Lysine withN_(α),N_(ε)-bis-lauroyl-L-lysine

A 1 liter beaker equipped with an overhead mechanical stainless steelpaddle stirrer was charged with 100 mL of 1 M NaOH (0.100 mol). Stirringwas initiated and the beaker cooled to −5° C. to −10° C. using asalt/ice bath. Next, 23.4 g (0.100 mol) of N_(ε)-benzylidene-L-lysine(prepared via the method of Bezas, B and Zervas, L., JACS, 83, 1961,719-722) was added. Immediately afterward and while keeping the solutioncold, 140 mL (0.140 mol) of precooled (in a salt/ice bath) 1 M NaOH and26.1 mL of lauroyl chloride was added in two equal portions over aperiod of 6 minutes. The mixture was stirred for 10 more minutes at −5to −10° C., then the ice bath was removed and the reaction mixtureallowed to stir for another 1 hour while warming to room temperature.Next, the reaction mixture was cooled using a salt/ice bath and thensufficient concentrated HCl was added to adjust the pH to 7.5-7.8. Withthe pH at 7.8-7.8 and with continued cooling and stirring, 4.6 mL (60%of stoichiometric, 0.068 mol) of thiophosgene was added drop-wise via anadditional funnel over the period of 1 hour. During this time,sufficient 1 M NaOH was added to maintain a pH range between 7.5-7.8.After the thiophosgene addition was complete, additional 1 M NaOH wasadded as necessary until the pH stabilized in 7.5-7.8 range. Next,sufficient 30% NaOH was added to adjust the pH to approximately 8.5.Next, 12 mL (0.051 mol) of lauroyl chloride was rapidly added, followedby sufficient 1 M NaOH to keep the pH in the range of 8.00-8.50. Next,sufficient concentrated HCl was added to adjust the pH to 1.5. Thereaction mixture was filtered via vacuum filtration, and the precipitatewashed with dilute HCl (pH=2). The product, a white moist solid, wasdried in vacuo while heating to 60° C. 45.19 g of white solid productwas recovered, a mixture of predominantlyN_(α)-lauroyl-N_(ε)-isothiocyanato-L-lysine andN_(α),N_(ε)-bis-lauroyl-L-lysine (determined via LC-MS analysis). Bothcompounds in this mixture can be simultaneously converted into anionic(carboxylate) surfactants via reaction with aqueous NaOH to yield aclear aqueous solution of the surfactants.

Example II Preparation of PureN_(α)-lauroyl-N_(ε)-Isothiocyanato-L-Lysine Step 1: Preparation ofN_(α)-lauroyl-N_(ε)-carbobenzoxy-L-Lysine

60.0 g of N_(ε)-cbz-L-Lysine (cbz—carbobenzoxy) purchased from AtomoleScientific Company, LTD was added to a three-liter beaker along with1200 mL of RO water and the mixture was stirred. Next, 39 mL of 30%aqueous NaOH was added, resulting in dissolution of theN_(ε)-cbz-L-Lysine. The resulting solution was cooled in an ice bath andthen 52.5 mL of lauroyl chloride was added. The ice bath was removed 30minutes later, and stirring continued for an additional six hours, atwhich time 18 mL of concentrated hydrochloric acid was added. Thereaction mixture was then filtered via vacuum filtration, the whitesolid product washed with 1 M aqueous HCl, and then the solid productwas dried in vacuo while heated to approximately 85° C. 96.5 g of drywhite solid product was obtained. The product is further purified bydissolving it in methanol, filtering off any insoluble precipitate, andremoving the methanol in vacuo to recover a white solid product (mp99.5-103.0° C.)

Step 2: Preparation of N_(α)-lauroyl-N_(ε)-ammonium Chloride-L-Lysine

10.0 g of N_(α)-lauroyl-N_(ε)-carbobenzoxy-L-Lysine was weighed into aone liter Erlenmeyer flask equipped with a magnetic stir bar. 150 mL ofconcentrated hydrochloric acid was added and the solution was stirredand heated in an oil bath to 104° C., then allowed to cool with the oilbath back to room temperature. The solution was then cooled to 9° C. forapproximately four hours, during which time a large mass of whiteprecipitate formed. The reaction mixture was filtered in vacuo andrinsed with a small amount of cold 1 M HCl. The white solid reactionproduct was then dried in vacuo while being heated to 78° C., yielding7.89 g of white solid product (mp 191-193° C.).

Step 3: Preparation of N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine

0.46 mL of thiophosgene was added to 30 mL of dichloromethane in a 125mL Erlenmeyer flask equipped with a magnetic stir bar. To this solutionwas drop wise added over 15 minutes a solution consisting of 2.00 gN_(α)-lauroyl-N_(ε)-ammonium chloride-L-Lysine, 10 mL RO water, and 2.7mL 20% aqueous NaOH. Stirring was continued for an additional 30minutes, after which sufficient concentrated hydrochloric acid was addedto lower the pH to 1 as indicated by testing with pHydrion paper. Thereaction solution was then transferred into a separatory funnel and thebottom turbid dichloromethane layer was isolated and dried withanhydrous magnesium sulfate and gravity filtered. To the filtrate wasadded 50 mL of hexanes. The solution was then concentrated via removalof 34 mL of solvent via trap-to-trap distillation and then placed in a−19° C. freezer. A mass of white precipitate formed after a few hoursand was isolated via vacuum filtration and then dried in vacuo for 2hours. 1.130 g of a slightly off white solid powder product was obtained[mp 37.0-39.0° C.; IR (cm⁻¹), 3301sb, 2923s, 2852s, 2184m, 2099s, 1721s,1650s, 1531s, 1456m, 1416w, 1347m, 1216m, 1136w]. Analysis (MidwestMicrolab, LLC): Calculated: C, 61.58%; H, 9.25%; N, 7.56%; 0, 12.95%; S,8.65%. Actual: C, 61.64%; H, 9.21%; N, 7.58%; 0, 13.01%; S, 8.55%.

Step 4: Isolation of SodiumN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysinate Via Lyophilization

0.147 g of N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine was combined andstirred with 2 g of RO water and 0.39 mL of 1.00 M NaOH in a 50 mLsingle neck round bottom flask and filtered into a 250 mL single neckround bottom flask to yield a clear pale amber solution. The flask wasthen immersed while rotating into a dry ice/acetone bath to yield asolid coating on the walls of the flask, whereupon the flask wasevacuated (0.10 mm Hg) and removed from the ice bath. Evacuation for onehour yielded a dry white solid powder of the water soluble surfactantSodium N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysinate. [mp 47-55° C. tosmall droplets of clear colorless viscous liquid; IR (mineral oil mull,cm⁻¹), 3300m amide N—H str; 2188s, 2107s N═C str; 1627s, amide C═O str;1593s carboxylate C═O str].

Example III Preparation of a Two-Part Formulation

A two-part formulation for topical application to the skin was preparedas follows:

Part I: A 25% by mass mixture ofN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine in Dow Corning DC344 fluid(a mixture of octamethyl-cyclotetrasiloxane anddecamethyl-cyclopentasiloxane) was prepared in a mortar and pestle toproduce a paste that was loaded into a 5 ml plastic disposable syringe.A syringe needle was not employed. Rather, the dispensing end of thesyringe was capped except for when dispensing without a syringe needleinto the palm of a hand occurred.

Part II: Part II consisted of Cetaphil Moisturizing Lotion to whichadditional triethanol amine (TEA) was added such that the concentrationof the additional triethanol amine was 0.006 g triethanol amine per gramof lotion, raising the pH of the Cetaphil Lotion from 7.74 to 8.77.

Preferred Instructions for Application of Formulation to the Skin: A 0.2mL portion of the N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine/DC344mixture is dispensed from the syringe into the palm of a hand(approximately 0.13 g of the mixture). Next, two full squirts of theCetaphil/TEA lotion is dispensed on top of theN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine/DC344 mixture (approximately2.8 g of the lotion). Next, using the index finger of the other hand,the components are mixed thoroughly for approximately 30 seconds, duringwhich time the water insolubleN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysine surfactant-precursor isdeprotonated to yield the water-soluble anionic (carboxylate) surfactantand yield a homogenous smooth white lotion (this reduces the pH to 7.4).This mixture is then applied to the afflicted areas by gently rubbing iton as one would apply any moisturizing lotion. Treatment is recommendedtwo to three times per day until the symptoms of the skin cancersubside.

Example IV Preparation of a One-Part Formulation I

A one-part formulation for topical application to the skin was preparedas follows:

First, 0.00025% (by wt.; 5.0 micromolar) of SodiumN_(α)-lauroyl-N_(ε)-isothiocyanate-L-Lysinate, the sodium salt of thematerial provided in step three of Example II, was associated with (QSto achieve 100%) 2,6,10,15,19,23-Hexamethyltetracosane (commerciallyavailable from Sigma-Aldrich). It will be understood that theconcentration of Sodium N_(α)-lauroyl-N_(ε)-isothiocyanate-L-Lysinatemay range from approximately 0.000001% to approximately 50%.Non-limiting examples of additional concentrations include 0.0005%,0.005%, 0.005%, 0.005%, 0.05%, 0.5%, 5%—just to name a few. It will befurther understood that the concentration of Lauryl PEG-10 Methyl EtherDimethicone may range from approximately 0.00001% to approximately 50%.

Preferred Instructions for Application of the One-Part Formulation tothe Skin: A 0.1-1.0 mL portion of the one-part formulation is dispensedfrom a container into the palm of a hand for subsequent administrationto an affected area and/or is dispensed directly onto an affected areaby gently rubbing it on as one would apply a moisturizing lotion.Treatment is recommended one to four times per day until the symptoms ofthe skin cancer subside.

Example V Preparation of a One-Part Formulation II

A one-part oil-based formulation for topical application to the skin wasprepared as follows:

Lyophilized Sodium N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysinate (0.15g) is dissolved in 29.85 g of refined jojoba oil while stirring andwarming to 50° C. to give a clear colorless solution that is 0.50% bymass Sodium N_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysinate. Next, 0.10 gof this solution was combined with 69.90 g of refined jojoba oil, 20.0 gof heavy mineral oil, and 10.0 g of squalane to yield an oil-basedformulation that is 0.00050% by mass SodiumN_(α)-lauroyl-N_(ε)-isothiocyanato-L-Lysinate. The oils employed areprovided for the purposes of illustration, and are not to be construedas limiting the invention in any way. As such, the oils may be liquid,solid, or gel, and may be synthetic or of natural origin and include butare not limited to waxes, esters, lipids, fats, glycerides, cyclicsilicones, linear silicones, crosslinked silicones, alkylsilicones,silicone copolyols, alkylated silicone copolyols, and/or hydrocarbons,and/or ethoxylated versions of all of these.

The foregoing description merely explains and illustrates the inventionand the invention is not limited thereto except insofar as the appendedclaims are so limited, as those skilled in the art who have thedisclosure before them will be able to make modifications withoutdeparting from the scope of the invention.

What is claimed and desired to be secured by Letters Patent of theUnited States is:
 1. A compound represented by the structure of formula(IA):

wherein R₁ is selected from the group consisting of the structures offormula (IIA), (IIIA), and (IVA);

wherein X is an integer ranging from 1 to 20; wherein R₂ is a linear orbranched aliphatic group containing 8 to 25 carbon atoms; and wherein R₃is an aliphatic or aromatic group containing 1 to 20 carbon atoms and atleast one—N═C═S group.
 2. The compound according to claim 1, wherein R₁is the structure of formula (IIA).
 3. The compound according to claim 2,wherein R₂ is an aliphatic group containing 12 to 20 carbon atoms. 4.The compound according to claim 1, wherein R₁ is the structure offormula (IIIA).
 5. The compound according to claim 4, wherein R₂ is analiphatic group containing 12 to 20 carbon atoms.
 6. The compoundaccording to claim 1, wherein R₁ is the structure of formula (IVA). 7.The compound according to claim 6, wherein R₂ is an aliphatic groupcontaining 12 to 20 carbon atoms.
 8. A compound represented by structureof formula (IB):

wherein R₁ is selected from the group consisting of the structures offormula (IIB), (IIIB), and (IVB);

wherein X is an integer ranging from 0 to 20; wherein R₂ is a linear orbranched aliphatic group containing 8 to 25 carbon atoms; wherein R₃ isan aliphatic or aromatic group containing 1 to 20 carbon atoms and atleast one—N═C═S group; and wherein M⁺ is selected from the groupconsisting of Li⁺, Na⁺, K⁺, and H⁺.
 9. The compound according to claim8, wherein R₁ is the structure of formula (IIB).
 10. The compoundaccording to claim 9, wherein R₂ is an aliphatic group containing 12 to20 carbon atoms.
 11. The compound according to claim 8, wherein R₁ isthe structure of formula (IIIB).
 12. The compound according to claim 11,wherein R₂ is an aliphatic group containing 12 to 20 carbon atoms. 13.The compound according to claim 8, wherein R₁ is the structure offormula (IVB).
 14. The compound according to claim 13, wherein R₂ is analiphatic group containing 12 to 20 carbon atoms.
 15. A formulation,comprising: a compound represented by the structure of formula (IB):

wherein R₁ is selected from the group consisting of the structures offormula (IIB), (IIIB), and (IVB);

wherein X is an integer ranging from 1 to 20; wherein R₂ is a linear orbranched aliphatic group containing 8 to 25 carbon atoms; wherein R₃ isan aliphatic or aromatic group containing 1 to 20 carbon atoms and atleast one—N═C═S group; wherein M⁺ is selected from the group consistingof Li⁺, Na⁺, K⁺, and H⁺; and a non-hygroscopic solvent.
 16. Theformulation according to claim 15, wherein R₁ is the structure offormula (IIB).
 17. The formulation according to claim 16, wherein R₂ isan aliphatic group containing 12 to 20 carbon atoms.
 18. The formulationaccording to claim 15, wherein R₁ is the structure of formula (IIIB).19. The formulation according to claim 18, wherein R₂ is an aliphaticgroup containing 12 to 20 carbon atoms.
 20. The formulation according toclaim 15, wherein R₁ is the structure of formula (IVB).
 21. Theformulation according to claim 20, wherein R₂ is an aliphatic groupcontaining 12 to 20 carbon atoms.